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Download Drosophila The Antimicrobial Defense of , A Paradigm for Innate Immunity
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The Antimicrobial Defense of Drosophila, A Paradigm for Innate Immunity Jules Hoffmann, Strasbourg, France Bacteria Viruses Protozoa Fungi Jos Hoffmann 1911-2000 Pierre Joly 1913-1996 Antimicrobial Defenses in Insects : First Investigations Metchnikoff Paillot Phagocytosis « Cellular Immunity » Metchnikoff, 1880 Antimicrobial substances in the blood « Humoral Immunity» Paillot 1920-1935 Glaser Induction of an antimicrobial activity in Drosophila by an immune challenge 1 Hyalophora cecropia Injection of bacteria Antimicrobial activity in the cell-free hemolymph 2 Hans Boman 1924-2008 3 Control 0 3 6 9 12 24 Time (h) 48 Systemic (“humoral”) antimicrobial response in Drosophila – identification of antimicrobial peptides P P P P GG P GG GGG G P G G G G G G G Diptericin G G G G G GG G G G Fat body cells P P P G G G P G G G G Metchnikowin G Attacin Cecropin Drosocin Defensin P NF-κB response elements in the promoter of the diptericin gene -1 kb enhancer -150 -140 -62 -31 coding sequence of the diptericin gene κB-Response element NLS 1 678 REL Stewart 1987 1 Ank DORSAL CACTUS Diptericin-LacZ reporter gene Unchallenged Challenged 482 Versailles, 18 years ago, Innate Immunity Conference Michael Zasloff Jean-Marc Reichhart Dan Hultmark Klas Kärre Danièle Hoffmann Charlie Janeway Shunji Natori Alan Ezekowitz Bob Lehrer Hans Boman Charles Hetru Ingrid Faye Gene cascade controlling the dorso-ventral axis in the Drosophila embryo CHORION Easter PERIVITELLIN SPACE Spätzle Snake EMBRYO Gastrulation Defective Windbeutel and Pipe Tube Toll Cactus Pelle Nudel FOLLICLE CELLS Christiane Nüsslein-Volhard Cell membrane Nuclear membrane Dorsal Do the genes of the Spätzle/Toll/Dorsal cassette control the challenge-induced expression of diptericin ? wild type Infection - 6h Tolldeficient - 6h P Diptericin P P P GG P GG GGG G P G G Diptericin 1990 rp49 G G G G G P P P P GG P GG GGG G P G G G G G G G Diptericin G G G G G GG G G G Fat body cells Drosomycin 1994 P P P G G G P G G G G Metchnikowin G Attacin Cecropin Drosocin Defensin P The challenge-induced expression of the Drosomycin gene is dependent on the Toll pathway. wild type Infection - 6h Tolldeficient - 6h Diptericin Drosomycin Drosomycin 1994 rp49 Two distinct pathways control the expression of antimicrobial peptides wild type Infection - 6h Tolldeficient Cactdeficient - - 6h imd - 6h Diptericin Drosomycin rp49 Toll Imd pathways Imd pathway mutants are sensitive to bacterial infections 100 of survival 80 60 wild type Imd mutants % 40 20 0 1 2 3 Time (days) 4 5 6 E. coli infection Toll pathway mutants are sensitive to fungal infections 100 % survival 80 60 Wild type Toll mutants 40 20 0 1 2 3 4 Time (days) 5 6 Aspergillus infection Overwhelming fungal infection in a Toll deficient background Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. Cell, 1996, 20:973-83 NF-κB activation by Toll and IL-1 Leucine rich repeat domains CD14 Leucine rich repeat domains Toll Ig-like domains IL-1R GPI anchor TIR domain NF-κB TIR domain NF-κB Cell membrane Activation of NF-κB by TLR family members Mycoplasmal Lipopeptide LPS Bacterial Lipopeptide Flagellin MD-2 TLR 2 TLR 4 TLR 6 TLR 2 TLR 1 TLR 5 Endosome Adaptor proteins (MyD88, TRIF, TIRAP,TRAM) NF-κΒ and IRFs Antimicrobial Peptides etc Activation of Adaptive Immune Responses TLR 3 dsRNA TLR 7 ssRNA CpG DNA TLR 9 Fungi Receptors Gram positive bacteria Proteolytic cascade Spaetzle Toll-4 Toll-5 Toll-6 Toll-3 Toll-7 Toll-2 Toll-8 Toll-9 Toll NF-κB A mutation in the PGRPSA gene (semmelweis) compromises the antiGram-positive defense Survival rate 100 A mutation in the PGRP-LC gene compromises the defense against Gramnegative bacteria Infection by Infection by Streptococcus faecalis Enterobacter cloacae 100 wt wt 50 50 seml PGRP-LC12 24 Time (h) 36 12 24 36 Time (h) Royet and coll. 2001, Royet, Ferrandon and coll., Anderson and coll., Ezekowitz and coll. 2002 48 A mutation in the gene encoding GNBP3 compromises resistance to Candida infections Survival (%) 100 80 wt Loss of function mutant of GNBP3 60 40 20 1 2 Time in days 3 4 Microbial Inducers of Immune Responses and Cognate Receptors in Flies: Peptidoglycan Recognition Proteins and Glucan Binding Proteins Peptidoglycan MurNAc GlcNAc MurNAc β-(1,3) -Glucan GlcNAc Glc Lys Lys DAP Glc DAP Glc Glc GNBP PGRP Roussel and coll. Werner and coll.; Kim and coll.; Reiser and coll.; Chang and coll. Microbial Fungi proteases (β-Glucan) PGRP-SA GNBP-3 Persephone (serine protease) Gram positive bacteria (LYS-PGN) Gram negative bacteria (DAP-PGN) Cascade of serine proteases Spaetzle PGRP-LC Toll NF-κB Dif Effector genes Relish Effector genes DD Imd NF-κB activation by Toll in Drosophila Microbial sensors Fungi Spz TOLL G+ bacteria Proteasome Spz MyD88 TIR DD DORSAL /DIF Drosomycin and hundreds of genes P PELLE KD Cactus TUBE Receptor/ adaptor complex NF-κB activation by IMD in Drosophila G- Bacteria Dredd Imd DD Ub FADD NF-κB / RELISH P IKK Signalosome P IKKβ P Tak1 Ub Tab2 IKKγ Ub Jnk pathway Diptericin and hundreds of genes Cytoskeletal proteins, proapoptotic signaling PGRP-LC TLR4 Toll Spaetzle LPS IMD TNF-α PGN Toll TLR4 PGRP MyD88 MyD88 Imd Pelle kinase IRAK IKK complex NF-κB (Dorsal, DIF) TNF-R RIP TAK1 NF-κB Cactus TNF NF-κB IκB NF-κB (p65/p65) TAK1 JNK IKK complex TAK1 JNK IKK complex NF-κB (Relish) NF-κB IκB NF-κB (cleaved Relish) NF-κB JNK Phylogeny of Innate Immune Defenses AMP AMP NF-κB NF-κB TAK1 TAK1 TOLL TOLL Sponges Sea anemones (Porifera) (Cnidaria) Radial diploblastic AMP AMP AMP NF-κB NF-κB NF-κB TAK1 TAK1 TAK1 TOLL TOLL TOLL Insects Echinoderms Hemichordates Worms Molluscs AMP NF-κB TAK1 TOLL Chordates ~ 450 million years Protostomes Deuterostomes Bilateral triploblastic Cambrian, ~ 550 million years Precambrian, ~ 600 million years Precambrian, ~ 800 million years Multicellularity origin ~1 billion years Acknowledgements D. Hoffmann C. Hetru JL. Dimarcq J.M. Reichhart B. Lemaitre D. Ferrandon J. Royet J.L. Imler E. Levashina M. Lagueux P. Bulet USA, Credits : Drosophila immunity Kathryn Anderson Carl Hashimoto Steve Wasserman Tony Ip Europe, Ruth Stewart Shuba Govind Hans Boman† Hakan Steiner Dan Hultmark Ingrid Faye Ylva Engström Ulli Theopold Neal Silverman Tom Maniatis Alan Ezekowitz Nathalie Franc Linda Stuart Christine Kocks Norbert Perrimon Herve Agaisse Michael Boutros David Schneider Bruno Lemaitre François Leulier Julien Royet Mika Ramet Nick Gay Asia, Shoichiro Kurata Won-Jae Lee Young-Joon Kim Acknowledgements D. Hoffmann C. Hetru B. Lemaitre JL. Dimarcq J.M. Reichhart D. Ferrandon M. Meister J.L. Imler E. Levashina M. Lagueux J. Royet P. Bulet The sea anemone Nematostella Nematostella Toll MyD88 TAK1 TLR TIR TRAF6 TIR MyD88 DD IKK Tak1 IKK NLS RHD G rich Ank repeats NF-κB IκB NF-κB IκB NF-κB Microbial ligands Cytokines Hypothetical receptor CD28 NF-κB B.7 TCR NF-κB Denditric cell (Antigen Presenting Cells…) MHC Peptide Naive T Cell Activation of adaptive immunity by innate immunity
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